Dual surface modification of polydimethylsiloxane (PDMS) with antithrombin-heparin complex (ATH) and tissue plasminogen activator (t-PA) for enhanced antithrombotic activity.

Medical devices used in contact with blood trigger coagulation and activate platelets leading to thrombotic complications. To prevent these effects, systemic anticoagulants and antiplatelet agents are typically prescribed, but these agents tend to increase the risk of bleeding. Modification of the surface of the blood-contacting material is an alternative approach to the inhibition of coagulation and thrombosis. In this work, the dual surface modification of polydimethylsiloxane (PDMS) with an antithrombin-heparin complex (ATH) to inhibit coagulation, and tissue plasminogen activator (t-PA) to lyse incipient clot, was investigated. Three different modification processes were used to immobilize ATH and t-PA: sequentially, with one component followed by the other; and with both components present simultaneously. Polydopamine (PDA) was used as a "bioglue" to enhance adhesion of the modifiers. The surface hydrophilicity and roughness were found to increase with increasing extent of modification. The surface density of the modifiers and their stability in plasma were significantly influenced by the modification process. The sequential method with t-PA first followed by ATH led to increased heparin activity. Data from plasma clotting time experiments showed that the combination of ATH and t-PA provides a synergistic effect, wherein both the anticoagulant activity of ATH and the clot lysis activity of t-PA on the surface are enhanced. This dual modification approach using both an anticoagulant and a thrombolytic agent shows promise to improve the blood compatibility of PDMS. The strategy can be applied to materials other than PDMS since the PDA coating is generic, thus providing a method for improving the performance of many blood-contacting devices.

[Survey on the State, Potential, and Obstacles of the Digital Transformation in Human Milk Banks]. / Stand, Potenzial und Barrieren der digitalen Transformation von Frauenmilchbanken: Eine Umfrange unter AnwenderInnen.

Digitalization of human milk banking was examined in a survey among participants of the largest German-speaking symposium for human milk banks. Of the 100 participants, 47% were nurses, 23% were physicians, and 3% were midwives. The overwhelming majority (96%) desired more digitalization in their milk bank. The best-digitized processes were clinical results from donors, milk labeling, and milk orders. At the same time, a discrepancy between the maximum conceivable potential and the current implementation of digital transformation became evident. The survey revealed most participants use in-house digital solutions. Potential main advantages of digitalization were cited as efficiency gains, while implementation efforts and security concerns, particularly power outages and cyberattacks, were seen as disadvantages. Financial restraints, personnel shortage, resistance from local IT departments, and legal concerns were perceived as the biggest barriers. Despite these challenges and a critical examination of the disadvantages, the participants expressed strong optimism and a desire for further digitalization in the human milk bank sector.

Fatty acids from nutrition sources for preterm infants and their effect on plasma fatty acid profiles.

BACKGROUND: In preterm infants, IV administration of fat is less well tolerated compared to intake via the enteral route, often resulting in hypertriglyceridemia. It is therefore recommended that parenteral fat intake should not exceed 3.5 to 4.0 g/kg/d whereas human milk can provide up to 8 g/kg/d. It is unknown whether such hypertriglyceridemic conditions are caused by a uniform increase of all fatty acids or it is linked to an elevation of distinct fatty acids due to an unbalanced intake. Obviously, both scenarios could potentially influence the formulation of novel lipid solutions for preterm infants. Objective of this exploratory study was to compare fatty acid profiles between a) different nutritional sources and corresponding plasma samples, b) plasma of infants fed breast milk versus those receiving lipid emulsion, and c) plasma of infants with normal versus elevated triglyceride levels. METHODS: Forty-seven preterm infants < 36 weeks of gestation were included; fatty acid profiles were measured in serum samples and corresponding nutritional sources (breast milk and lipid emulsion) using gas chromatography/mass spectrometry. RESULTS: Compared to breast milk levels, plasma contained significantly lower C8:0, C10:0, C12:0, C14:0, C19:1n9, C18:3n3 (p < 0.0001). In contrast, relative abundance of C16:0, C18:0 and C20:4n6 was higher in plasma than in corresponding breast milk samples (p < 0.001) and lipid emulsion (p < 0.01). Compared to the corresponding lipid emulsion, the abundance of C18:2n6 and C18:3n3 was significantly lower in plasma (p < 0.001). Fatty acid profiles in plasma of infants fed breast milk compared to lipid emulsion were not markedly different. Hypertriglyceridemic samples showed elevated levels for C18:1n9 and C16:0 when compared with normotriglyceridemic samples. CONCLUSIONS: Our study reveals that lipid levels in plasma show both depletion and enrichment of distinct fatty acids which do not seem to be closely related to dietary intake. A more detailed understanding of fatty acid flux rates is needed, like the understanding of amino acid metabolism and is supported by the finding that hypertriglyceridemia might be a state of selective fatty acid accumulation. This would allow to develop more balanced diets for intensive care and potentially improve clinical outcomes.

Body Composition Analysis of the Clinical Routine Using Air Displacement Plethysmography: Age-Group-Specific Feasibility Analysis among Preterm Infants.

Body composition assessments using air displacement plethysmography (ADP, PEAPOD®) have been introduced into clinical practice at a few neonatal units. To allow accurate body composition assessments in term and preterm infants, a workflow for routine testing is needed. The aim of this study was to analyze the feasibility of weekly routine ADP testing. We analyzed (1) postnatal ages at first ADP assessment, (2) the number of weekly routine in-hospital assessments, and (3) the workload of body composition measurements using ADP in clinical practice on the basis of an retrospective analysis of our own clinical operating procedures. The retrospective analysis of weekly routine ADP testing proved feasible at Nuremberg Children's Hospital. The analysis of postnatal age at the first ADP test revealed differences across groups, with extremely preterm infants starting at a mean postmenstrual age of 36.6 weeks, very preterm infants starting at 34.2 weeks, and moderate to late preterm infants starting at 35.3 weeks. The mean number of tests before discharge was significantly greater in the extremely preterm group (n = 3.0) than in the very preterm (n = 2.4) and moderate to late preterm groups (n = 1.7). The workload of the procedure is reasonable, at 8-13 min per test cycle. The study proved that weekly routine ADP assessments in preterm infants are feasible. However, the initiation of routine testing in extremely preterm infants starts at a significantly greater postnatal age than in the more mature population. ADP assessments can be safely and easily integrated into clinical practice and may be valuable tools for providing additional information on nutritional status and infant growth. A standardized routine protocol allowing identical measurement conditions across healthcare institutions and a standardized interpretation tool for age-adapted body composition data, however, would improve comparability and usability.

Reproducibility of Air Displacement Plethysmography in Term and Preterm Infants-A Study to Enhance Body Composition Analysis in Clinical Routine.

The quality-initiative analysis of weekly duplicate PEAPOD® body composition measurements was conducted from clinical practice (January to September 2021) on preterm and term infants without respiratory support. Statistical analysis, including regression analysis, Bland-Altman plots and cv-root-mean-square tests, was performed. A total of 188 duplicate (376 individual) measurements were collected from 119 infants (88 preterm, 31 term). The median absolute difference between duplicates was 31.5 g for fat-free mass (FFM). Linear correlation analysis showed R2 = 0.97 for FFM. The absolute differences in FFM and fat mass did not significantly correlate with increasing age. The %FFM differed (p = 0.02) across body weight groups of 1 kg < BW ≤ 2 kg (1.8%; IQR: 0.8, 3.6) and BW > 3 kg (0.9%; IQR: 0.3, 2.1). The median absolute differences were 1 g (IQR: 0.4, 3.1) for body weight and 5.6 mL (IQR: 2.1, 11.8) for body volume. Body volume estimation is charged with a constant absolute error, which is the main factor for differences between repeated body composition assessments. This error becomes more prominent in infants with lower body weights. Nevertheless, reproducibility of weekly PEAPOD testing is sufficient to monitor body compartment changes, offering a foundation for nutritional decisions in both preterm and term infants.

Scaled-up Microfluidic Lung Assist Device for Artificial Placenta Application with High Gas Exchange Capacity.

Premature neonates with underdeveloped lungs experience respiratory issues and need respiratory support, such as mechanical ventilation or extracorporeal membrane oxygenation (ECMO). The "artificial placenta" (AP) is a noninvasive approach that supports their lungs and reduces respiratory distress, using a pumpless oxygenator connected to the systemic circulation, and can address some of the morbidity issues associated with ECMO. Over the past decade, microfluidic blood oxygenators have garnered significant interest for their ability to mimic physiological conditions and incorporate innovative biomimetic designs. Achieving sufficient gas transfer at a low enough pressure drop for a pumpless operation without requiring a large volume of blood to prime such an oxygenator has been the main challenge with microfluidic lung assist devices (LAD). In this study, we improved the gas exchange capacity of our microfluidic-based artificial placenta-type LAD while reducing its priming volume by using a modified fabrication process that can accommodate large-area thin film microfluidic blood oxygenator (MBO) fabrication with a very high gas exchange surface. Additionally, we demonstrate the effectiveness of a LAD assembled by using these scaled-up MBOs. The LAD based on our artificial placenta concept effectively increases oxygen saturation levels by 30% at a flow rate of 40 mL/min and a pressure drop of 23 mmHg in room air, which is sufficient to support partial oxygenation for 1 kg preterm neonates in respiratory distress. When the gas ambient environment was changed to pure oxygen at atmospheric pressure, the LAD would be able to support premature neonates weighing up to 2 kg. Furthermore, our experiments reveal that the LAD can handle high blood flow rates of up to 150 mL/min and increase oxygen saturation levels by ∼20%, which is equal to an oxygen transfer of 7.48 mL/min in an enriched oxygen environment and among the highest for microfluidic AP type devices. Such performance makes this LAD suitable for providing essential support to 1-2 kg neonates in respiratory distress.

Analysis of noise levels in the neonatal intensive care unit: the impact of clinical microsystems.

Reorganization of neonatal intensive care by introducing clinical microsystems may help to allocate nursing time more appropriately to the needs of patients. However, there is concern that cohorting infants according to acuity may enhance noise levels. This single-center study investigated the impact of reorganization of neonatal intensive care unit by implementing clinical microsystems in a Level III NICU on environmental noise. This prospective study measured 24-h noise levels over a period of 6 months during pre- and post-implementation of microsystems cohorting infants of similar acuity. Comparative analyses of the mixed acuity (i.e., before) and the cohorting (i.e., after) model were performed by creating daily profiles from continuous noise level measurements and calculating the length of exposure to predefined noise levels. Compared to baseline daytime measurements, noise levels were 3-6 dBA higher during physician handover. Noise levels were 2-3 dBA lower on weekends and 3-4 dBA lower at night, independent of the organizational model. The introduction of clinical microsystems slightly increased average noise levels for high-acuity pods (A and B) but produced a much more substantial decrease for low-acuity pods (E), leading to an overall reduction in unit-wide noise levels.    Conclusion: Our data show that noise levels are more driven by human behavior than by technical devices. Implementation of microsystems may help to reduce noise exposure in the lower acuity pods in a NICU. What is Known: • Excessive noise levels can lead to adverse effects on the health and development of premature infants and other critically ill newborns. • The reorganization of the neonatal intensive care unit following the clinical microsystems principles might improve quality of care but also affect noise exposure of staff and patients. What is New: • The transition from a mixed -acuity to cohorting model is associated with an overall reduction in noise levels, particularly in low-acuity pods requiring less nursing care. • Nevertheless, baseline noise levels in both models exceeded the standard permissible limits.

[Operating models and organizational structures: opportunities and challenges for human milk banking in Germany]. / Versorgungsstrukturen und Betreibermodelle: Chancen und Herausforderungen des Frauenmilchbankwesens in Deutschland.

BACKGROUND: Donor human milk is the recommended alternative for feeding preterm infants if mother's own milk is unavailable. Human milk banks collect, screen, store and distribute donated human milk according to pre-specified standard operating procedures to premature infants without mothers own milk. AIM: Herein we characterize current operating models and the structural organisation of German milk bank institutions. The analysis of current and future opportunities and challenges may support the development of a comprehensive donor milk service within Germany. MATERIAL AND METHODS: Summary of the panel discussion entitled "Operating models and organizational structures: opportunities and risks for donor human milk bank in Germany" during the 3rd Scientific Symposium of the German Human Milk Bank Initiative (FMBI), November 25th to 26th 2022, in Nuremberg, Germany. RESULTS AND DISCUSSION: Differing operator models may facilitate the use of donor human milk by incorporating unique site-specific factors, pre-existing infrastructure, and individual needs. In addition to the establishment of milk banks serving single neonatal units, high-capacity milk banks should be enabled to provide donor human milk using several hub-and-spoke systems. This may create a nationwide network for a sustainable human milk supply for preterm infants that is based on qualified breastfeeding and lactation support.

Nutrition of the preterm infant with persistent ductus arteriosus: existing evidence and practical implications.

The persistence of a patent ductus arteriosus (PDA) is a common condition in preterm infants with a prevalence inversely proportional to gestational age. PDA is associated with mild-to-severe gastrointestinal complications such as feeding intolerance, gastrointestinal perforation, and necrotizing enterocolitis, which represent a major challenge for the nutritional management in preterm infants. In this context, the Section on Nutrition, Gastroenterology and Metabolism and the Circulation Section of the European Society for Pediatric Research have joined forces to review the current knowledge on nutritional issues related to PDA in preterm infants. The aim of the narrative review is to discuss the clinical implications for nutritional practice. Because there is little literature on postnatal nutrition and PDA in preterm infants, further research with well-designed studies on this topic is urgently needed. Guidelines should also be developed to clearly define the implementation and course of enteral nutrition and the target nutritional intake before, during, and after pharmacologic or surgical treatment of PDA, when indicated. IMPACT: Persistent ductus arteriosus (PDA) is associated with gastrointestinal complications such as feeding intolerance, gastrointestinal perforation, and necrotizing enterocolitis, which pose a major challenge to the nutritional management of preterm infants. In PDA infants, fluid restriction may lead to inadequate nutrient intake, which may negatively affect postnatal growth and long-term health. The presence of PDA does not appear to significantly affect mesenteric blood flow and splanchnic oxygenation after enteral feedings. Initiation or maintenance of enteral nutrition can be recommended in infants with PDA.

"Multisystem Inflammatory Syndrome in Children" (MIS-C) after COVID-19 Infection in the Metropolitan Area of Nuremberg-Erlangen, Germany-Expectations and Results of a Two-Year Period.

BACKGROUND: Multisystemic Inflammatory Syndrome in children (MIS-C) is a rare autoimmune disorder occurring after a latency period following acute SARS-CoV-2 infection. The therapeutic regime of MIS-C is adapted to the therapy of the Kawasaki disease, as clinical symptoms are similar. Since the Kawasaki disease can potentially result in severe symptoms, which may even affect long-term health, it is essential to gain further knowledge about MIS-C. Thus, we aimed to investigate the incidence, symptoms, therapeutical procedure and outcome of MIS-C patients in the metropolitan area of Nuremberg-Erlangen during the SARS-CoV2 pandemic. MATERIAL AND METHODS: Retrospective analysis of clinical charts of MIS-C patients was carried out at three children's hospitals covering the medical care of the metropolitan area of Nuremberg-Erlangen in Germany. Demographic characteristics and symptoms at first visit, their clinical course, therapeutic regime and outcome were recorded within the time period January 2021-December 2022. RESULTS: Analysis of 10 patients (5 male, 5 female) with MIS-C resulting in an incidence of 2.14/100.000 children. The median time between COVID-19 infection and admission to hospital was 5 weeks. The median age was 7 years. Symptoms comprised fever (100%), rash (70%), bilateral non-purulent conjunctivitis (70%) and urticaria (20%). At the time of presentation, diagnosis-defining inflammation parameters were increased and the range for C-reactive protein was 4.13 mg/dL to 28 mg/dL, with a median of 24.7 mg/dL. Procalcitonin was initially determined in six patients (1.92 ng/mL to 21.5 ng/mL) with a median value of 5.5 pg/mL. Two patients displayed leukocytosis and two displayed leukopenia. None of the patients presented coronary pathologies. Nine of the ten patients received intravenous immunoglobulin (IVIG) therapy. In addition, patients received intravenous steroids (80%) and acetylsalicylic acid (80%). CONCLUSION: SARS-CoV virus may rarely exert multiorgan manifestations due to hyperinflammatory immunological processes. Within two years of the COVID-19 pandemic, we identified ten patients with COVID-induced MIS-C in the metropolitan area Nuremberg-Erlangen. In the description of the patient collective, we can confirm that MIS-C is distinguished from the Kawasaki disease by the lack of coronary manifestations. Interestingly, although having monitored all pediatric facilities in the investigated area, we find lower incidences of MIS-C compared to findings in the literature. In conclusion, an overestimation of incidences in the upcoming MIS-C during the pandemic needs to be considered.

Care Bundle to Improve Oxygen Maintenance and Events.

Prolonged periods spent outside the target range of oxygen saturation (SpO2) in preterm infants, along with frequent desaturation events, predispose them to retinopathy of prematurity (ROP) and long-term neurodevelopmental impairment. The primary aim of this study was to increase the mean time spent within the target SpO2 range (WTR) by 10% and to reduce the frequency of desaturation events by 5 events per patient day, respectively, within 18 months of implementing a care bundle. Methods: This study was completed in a 46-bed neonatal intensive care unit (NICU), involving 246 staff members and led by a quality improvement team. The change interventions included implementing new practice guidelines, reviewing daily summaries of SpO2 maintenance, daily infant wellness assessment, standardizing workflow, and responding to SpO2 alarms. In addition, we collected staff satisfaction and compliance with change interventions, resource use, and morbidity and mortality data at discharge. Results: The mean time spent WTR increased from 65.3% to 75.3%, and the frequency of desaturation events decreased from 25.1 to 16.5 events per patient day, respectively, with a higher magnitude of benefit in infants on days with supplemental oxygen. Postimplementation, the duration of high-frequency ventilation and supplemental oxygen were lower, but morbidity and mortality rates were similar. Staff satisfaction with training workshops, coaching, use of the infant wellness assessment tool, and SpO2 alarm management algorithms were 74%, 82%, 80%, and 74%, respectively. Conclusion: Implementing a care bundle to improve oxygen maintenance and reduce desaturation events increased the time spent WTR and reduced the frequency of desaturation events.

Umbilical catheter placement aided by coronary guidewires.

Catheterization of the umbilical vessels has proven to be an effective and relatively rapid method for gaining central vascular access in neonates. However, it can be technically difficult, the procedure may last 30 min or longer, and it can be associated with complications in some patients. We suggest using a coronary guidewire during catheterization of umbilical vessels to support the placement of umbilical catheters and significantly reduce a risk for complications. We tested the proposed technique in 6 successful ex vivo bench tests of catheterization of the umbilical vessels in stillborn piglets immediately after birth. We are confident that using coronary guidewire as a guiding tool during catheterization of the umbilical vessels is a rapid and safe method. We expect that it allows to obtain a vascular access with lower risk for dangerous procedural complications, which could be a lifesaving in critically ill patients. However, the approach needs to be validated in a comparative study in neonates.

Enteral Nutrition in Preterm Infants (2022): A Position Paper From the ESPGHAN Committee on Nutrition and Invited Experts.

OBJECTIVES: To review the current literature and develop consensus conclusions and recommendations on nutrient intakes and nutritional practice in preterm infants with birthweight <1800 g. METHODS: The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee of Nutrition (CoN) led a process that included CoN members and invited experts. Invited experts with specific expertise were chosen to represent as broad a geographical spread as possible. A list of topics was developed, and individual leads were assigned to topics along with other members, who reviewed the current literature. A single face-to-face meeting was held in February 2020. Provisional conclusions and recommendations were developed between 2020 and 2021, and these were voted on electronically by all members of the working group between 2021 and 2022. Where >90% consensus was not achieved, online discussion meetings were held, along with further voting until agreement was reached. RESULTS: In general, there is a lack of strong evidence for most nutrients and topics. The summary paper is supported by additional supplementary digital content that provide a fuller explanation of the literature and relevant physiology: introduction and overview; human milk reference data; intakes of water, protein, energy, lipid, carbohydrate, electrolytes, minerals, trace elements, water soluble vitamins, and fat soluble vitamins; feeding mode including mineral enteral feeding, feed advancement, management of gastric residuals, gastric tube placement and bolus or continuous feeding; growth; breastmilk buccal colostrum, donor human milk, and risks of cytomegalovirus infection; hydrolyzed protein and osmolality; supplemental bionutrients; and use of breastmilk fortifier. CONCLUSIONS: We provide updated ESPGHAN CoN consensus-based conclusions and recommendations on nutrient intakes and nutritional management for preterm infants.

Make Bayley III Scores Comparable between United States and German Norms-Development of Conversion Equations.

AIM: Bayley Scales of Infant and Toddler Development (Bayley-III) determines scaled scores and converts these into composite scores. It was shown that applying the German and the U.S. manual leads to different results. This study aims to systematically analyze the differences between the U.S. and German Bayley-III version and to develop conversion equations. METHODS: This simulation study generated a dataset of pairs of U.S. and German Bayley-III composite scores (cognitive: n = 4,416, language: n = 240,000, motor: n = 314,000) by converting the same number of achievable tasks for 48 age groups. Bland-Altman plot and regression analyses were performed to develop conversion equations for all age groups. RESULTS: German and US Bayley-III scores demonstrate distinct slope and interception for cognitive, language, and motor composite scores. Lower developmental performance leads to higher composite scores with U.S. norms compared with German norms (up to 15 points). These differences varied between age groups. With newly developed conversion equations, the results can be converted (R 2 > 0.98). INTERPRETATION: This study confirms systematic differences between U.S. and German Bayley test results due to different reference cohorts. Our data consider the full age range and add conversion equations. These findings need to be acknowledged when comparing Bayley Scores internationally.

[Process for the Implementation of Evidence-Based Parenteral Nutrition in German Perinatal Centres - Outcomes of a Multidisciplinary Network]. / Prozess zur Implementierung Evidenzbasierter Parenteraler Ernährung in Deutschen Perinatalzentren ­ Ergebnisse eines Multidisziplinären Netzwerks.

INTRODUCTION: Parenteral nutrition, usually indicated for preterm infants with a birthweight<1500 g and sick newborns, enables the supply with critical nutrients. As a high degree of therapy safety is required, a European guideline provides recommendations for safe therapy procedures. The present project aimed to evaluate the implementation of the European guideline in German perinatal centers and to identify possible barriers that impede its implementation. A further goal was to develop solution approaches to overcome possible barriers. METHODS AND RESULTS: A multidisciplinary cooperation conducted an online survey questioning the current implementation procedures of the European guideline among pediatricians and hospital pharmacists. Results show barriers in the provisioning process of parenteral nutrition that hinder a guideline-compliant implementation in practice. Based on results of this survey, an expert network developed an interactive toolkit with simplified guideline recommendations, guideline-compliant advice for practice, best-practice examples, forms, and handouts. It seeks to encourage critical reflection of routine processes and provides concrete solutions to overcome barriers in practice. CONCLUSION: The current procedures related to parenteral nutrition deviate from guideline recommendations. The developed toolkit provides practice-oriented support aiming to enhance the guideline-compliant implementation of parenteral nutrition in perinatal centers.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) I-Cognitive Function and Metabolic Risk.

Neonatal nutritional supplements are widely used to improve growth and development but may increase risk of later metabolic disease, and effects may differ by sex. We assessed effects of supplements on later development and metabolism. We searched databases and clinical trials registers up to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter cognitive impairment in toddlers (13 trials, n = 1410; adjusted relative risk (aRR) 0.88 [95% CI 0.68, 1.13]; p = 0.31) or older ages, nor alter metabolic risk beyond 3 years (5 trials, n = 438; aRR 0.94 [0.76, 1.17]; p = 0.59). However, supplementation reduced motor impairment in toddlers (13 trials, n = 1406; aRR 0.76 [0.60, 0.97]; p = 0.03), and improved motor scores overall (13 trials, n = 1406; adjusted mean difference 1.57 [0.14, 2.99]; p = 0.03) and in girls not boys (p = 0.03 for interaction). Supplementation lowered triglyceride concentrations but did not affect other metabolic outcomes (high-density and low-density lipoproteins, cholesterol, fasting glucose, blood pressure, body mass index). Macronutrient supplementation for infants born small may not alter later cognitive function or metabolic risk, but may improve early motor function, especially for girls.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) II: Growth.

Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. We assessed the effects of early macronutrient supplements on later growth. We searched databases and clinical trials registers from inception to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter BMI in childhood (kg/m2: adjusted mean difference (aMD) -0.11[95% CI -0.47, 0.25], p = 0.54; 3 trials, n = 333). Supplementation increased length (cm: aMD 0.37[0.01, 0.72], p = 0.04; 18 trials, n = 2008) and bone mineral content (g: aMD 10.22[0.52, 19.92], p = 0.04; 6 trials, n = 313) in infancy, but not at older ages. There were no differences between supplemented and unsupplemented groups for other outcomes. In subgroup analysis, supplementation increased the height z-score in male toddlers (aMD 0.20[0.02, 0.37], p = 0.03; 10 trials, n = 595) but not in females, and no significant sex interaction was observed (p = 0.21). Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplementation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls.

Metabolic-endocrine disruption due to preterm birth impacts growth, body composition, and neonatal outcome.

Despite optimized nutrition, preterm-born infants grow slowly and tend to over-accrete body fat. We hypothesize that the premature dissociation of the maternal-placental-fetal unit disrupts the maintenance of physiological endocrine function in the fetus, which has severe consequences for postnatal development. This review highlights the endocrine interactions of the maternal-placental-fetal unit and the early perinatal period in both preterm and term infants. We report on hormonal levels (including tissue, thyroid, adrenal, pancreatic, pituitary, and placental hormones) and nutritional supply and their impact on infant body composition. The data suggest that the premature dissociation of the maternal-placental-fetal unit leads to a clinical picture similar to panhypopituitarism. Further, we describe how the premature withdrawal of the maternal-placental unit, neonatal morbidities, and perinatal stress can cause differences in the levels of growth-promoting hormones, particularly insulin-like growth factors (IGF). In combination with the endocrine disruption that occurs following dissociation of the maternal-placental-fetal unit, the premature adaptation to the extrauterine environment leads to early and fast accretion of fat mass in an immature body. In addition, we report on interventional studies that have aimed to compensate for hormonal deficiencies in infants born preterm through IGF therapy, resulting in improved neonatal morbidity and growth. IMPACT: Preterm birth prematurely dissociates the maternal-placental-fetal unit and disrupts the metabolic-endocrine maintenance of the immature fetus with serious consequences for growth, body composition, and neonatal outcomes. The preterm metabolic-endocrine disruption induces symptoms resembling anterior pituitary failure (panhypopituitarism) with low levels of IGF-1, excessive postnatal fat mass accretion, poor longitudinal growth, and failure to thrive. Appropriate gestational age-adapted nutrition alone seems insufficient for the achievement of optimal growth of preterm infants. Preliminary results from interventional studies show promising effects of early IGF-1 supplementation on postnatal development and neonatal outcomes.

Individualized Target Fortification of Breast Milk: Optimizing Macronutrient Content Using Different Fortifiers and Approaches.

Background: Native breast milk composition displays significant inter- and intra-individual variation which persists after standard fortification with fixed doses and challenges target fortification. This study aims to analyze the macronutrient composition of different commercially available fortifiers and the effect of different fortification strategies on nutritional intake of preterm infants. Methods: In 103 preterm infants, native breast milk samples were collected from 24-h feeding batches (n = 3,338) and fat, protein and carbohydrate contents were analyzed. Nutrient content was compared for breast milk that had undergone either (i) standard fortification, (ii) targeted fortification, (iii) selective batching according to breast milk composition, or (iv) partial lyophilization. For (i) eight commercially available standard fortifiers were tested. Targeted fortification (ii) involved the addition of single component modulars of either protein, fat or carbohydrates to standard fortified breast milk. Using a mathematical growth model, the combined effect of protein, fat and carbohydrate intake on growth was assessed. The best composition of standard fortifiers as the initial step for target fortification was explored assuming three clinical scenarios for milk analysis. Results: Macronutrient content was highly variable between native breast milk samples, and this variation was still present after standard fortification, however at elevated macronutrient levels. Standard fortification, breast milk batching, as well as partial lyophilization of human milk resulted in deficient and imbalanced enteral intakes in a significant proportion of infants. Target fortification reduced this variation in a, respectively, higher percentage of samples. The effect size was dependent on the number of measurements per week. The optimum composition of standard fortifiers was dependent on the clinical scenario (measurement frequency) for target fortification. Conclusions: To provide precise and accurate intakes of macronutrients, breast milk should be target fortified. Standard fortified breast milk can result in excess above recommended intakes of some macronutrients which limits the efficiency of target fortification. Standard fortifiers with improved composition are needed for target fortification.